The β-nitrostyrene compound represented by the following formula is a useful intermediate for producing a therapeutic drug for treating reflux esophagitis, an antispasmodic and the like, such as baclofen.
(in the above formula, n represents an integer of 0 to 3, and n Rs may be identical or different and each may represent a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a haloalkyl group, or a cycloalkyloxy group, or when n represents 2 or 3, two Rs may together form an alkylenedioxy group.)
Some of the methods for synthesizing such a β-nitrostyrene compound are conventionally known. For example, Japanese Patent Laying-Open No. 09-194457 (Patent Document 1), Japanese Patent Laying-Open No. 11-71348 (Patent Document 2), Japanese Patent National Publication No. 2001-510827 (Patent Document 3), and the like disclose the method for synthesizing a β-nitrostyrene compound by the heating and refluxing process using ammonium acetate as a base. However, in the case where ammonium acetate is used in this way, the reaction temperature is required to be set at a temperature close to its boiling point.
Furthermore, for example, the method disclosed in each of Japanese Patent Laying-Open No. 2002-241364 (Patent Document 4) and J. Am. Chem. Soc. (2005, 127, 119-125) (Non-Patent Document 1) is also known as a method for synthesizing a β-nitrostyrene compound. For example, Patent Document 1 discloses that a β-nitrostyrene compound can be produced at a yield of 67% under reflux conditions by using nitroalkane as a solvent and benzylamine as a base. However, also in this method, a reaction occurs at the heating temperature close to its boiling point.
Since the β-nitrostyrene compound is produced by the reaction using a nitro compound, it is feared that the reaction may, for example, get out of control. Thus, the reaction occurring at the heating temperature close to the boiling point may cause a problem in practical implementation from an industrial point of view. For example, when the β-nitrostyrene compound is actually produced, the residence time of the reaction solution of nitromethane and benzaldehyde is about 12 hours. As for the reaction solution of nitromethane and benzaldehyde, when the operating temperature is at 95° C., the time taken for the velocity of the self reaction in the adiabatic system to reach its maximum value (excursion) is 7.9 hours according to the measurement by an accelerating rate calorimeter (ARC).
Consequently, there is a need to provide a method for producing a β-nitrostyrene compound at a high yield by the reaction of nitromethane and benzaldehyde in the temperature range which is regarded as safe from an industrial point of view.    Patent Document 1: Japanese Patent Laying-Open No. 09-194457    Patent Document 2: Japanese Patent Laying-Open No. 11-71348    Patent Document 3: Japanese Patent National Publication No. 2001-510827    Patent Document 4: Japanese Patent Laying-Open No. 2002-241364    Non-Patent Document 1: J. Am. Chem. Soc. 2005, 127, 119-125